Ambroxol
Ambroxol is represented as a pharmacological chaperone / GBA activator strategy. The pilot source emphasizes ER folding, lysosomal delivery, GCase activity/protein readouts, alpha-synuclein, cognition, and mutation-dependent limitations. Sources: 20240722_181752, 20240722_181756.
Mechanism
| mechanism point | source-captured detail | source |
|---|---|---|
| Binding site | Ambroxol binds amino-acid segments 243-249, 310-312, and 386-400 near the active site of GCase. | 20240722_181752 |
| Folding / ER logic | Source describes stabilization of mutant GCase native conformation in the ER and prevention of misfolding, followed by escape from ER-associated degradation and lysosomal transport. | 20240722_181752 |
| pH logic | Ideal pharmacological chaperone binds at neutral ER pH and minimally at acidic lysosomal pH. | 20240722_181752 |
| Limitation | Source states null mutations are not useful targets for this approach. | 20240722_181752 |
Preclinical / Ex Vivo Evidence
| model / source row | key source note | source |
|---|---|---|
| L444P/1 mice | Ambroxol increased GCase activity in brainstem, midbrain, cortex, and striatum in wild-type and L444P transgenic mice; source notes baseline GBA activity was not very low. | 20240722_181752 |
| SNCA/SNCA mice | GBA activity increased less than 10%; phosphorylated alpha-synuclein decreased about 40%; memory improved in novel object recognition. | 20240722_181752 |
| Normal mice | Increased GBA activity in brain, spleen, and heart. | 20240722_181752 |
| GBA-PD fibroblast | Ambroxol increased cathepsin D activity, GCase and Sap C protein levels in all groups; LIMP-2 increased only in GBA1-mutant PD fibroblast. | 20240722_181752 |
| GD fibroblast | Ambroxol increased multiple mutant beta-glucosidase activities including N370S, F213I, N188S/G193W, and R120W. | 20240722_181752 |
Figures retained in the source page include ambroxol preclinical plots and an AD/PD 2021 GBA activity plot. Source: 20240722_181752.
Clinical Trial Map
| study / population | source-captured design | endpoints / notes | source |
|---|---|---|---|
| GD1, suboptimal ERT response | Ongoing, single-group open-label, 12 months, n=60, NCT03950050 | Platelet count, BMD, GlcSph. | 20240722_181752 |
| PDD, Lawson / Western Ontario | Ambroxol vs placebo, randomized double-blind, 52 weeks, n=75, NCT02914366 | Primary ADAS-cog; secondary UPDRS III, cognitive scales, CSF alpha-syn/tau/p-tau/Abeta42, MRI, GCase in lymphocytes, MRS. AD/PD 2021 note: dose-dependent WBC GBA activity increase. | 20240722_181752 |
| GD type 1, Exsar | Suspended, single-group open-label, 2 months, n=20, NCT01463215 | Safety plus GBA activity, organ volumes, and lab markers. | 20240722_181752 |
| nGD Narita | Ambroxol + ERT; patients selected for chaperone response in fibroblasts | Target 25 mg/kg/day or max 1300 mg/day; source notes GlcSph normalization not required and post-treatment GBA activity may remain low. | 20240722_181752, 20240722_181756 |
| nGD AMC / Kim 2020 | Ambroxol + ERT, all prior ERT, mean mSST 12.3 | After higher serum exposure, leukocyte residual GBA activity rose 5.1% to 13.7%; GlcSph nearly normalized in dried blood spot; several neurological symptoms improved, but saccades and brain MRS did not. | 20240722_181752 |
| AMBITIOUS P2 | Italy, NCT05287503, EudraCT 2021-004565-13; 52-week treatment | Primary MoCA change and conversion to MCI/dementia; source includes sample-size logic for 60 patients. | 20240722_181756 |
| ASPro-PD P3 | UCL, NCT05778617 | Source row mentions GBA-PD, ambroxol vs placebo, 52 weeks, and separately a 2-year placebo-controlled primary MDS-UPDRS I+II+III row. Alignment is uncertain. | 20240722_181756 |
| AiM-PD P2 | UCL, NCT02941822; single-group open-label, 6 months, 20 PD patients including GBA-positive and GBA-negative | Primary GBA activity and ambroxol levels in blood/CSF. Source notes CSF GBA protein increased 135%, CSF GBA activity decreased 19%, WBC GBA activity transiently increased, CSF total alpha-syn increased 13%, and MDS-UPDRS III decreased by 6.8 points. | 20240722_181756 |
Uncertainties Carried From Source
| issue | source |
|---|---|
Amino-acid binding segment 386-400 is high-risk numeric transcription. | 20240722_181752 |
| Korean mechanism note about normal/mutant GBA protein quantities is low-resolution. | 20240722_181752 |
| AMBITIOUS EudraCT number is reconstructed across short wrapped lines. | 20240722_181756 |
ASPro-PD row alignment is uncertain for N=330, treatment duration, and primary endpoint. | 20240722_181756 |
AiM-PD genotype shorthand RecNcil may be a visual/OCR ambiguity. | 20240722_181756 |